# Physiological Dissection of the Mevalonate Pathway

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $532,092

## Abstract

PROJECT SUMMARY
Statins are the only lipid lowering agents consistently shown to reduce the risk of death from cardiovascular
disease as a monotherapy. Currently, it is estimated that greater than 39.2 million adults in the United States are
on statins, and new may further increase the number of users in the U.S. alone to 56.0 million. This underscores
the importance of understanding the genetic basis of statin responsiveness as well as adverse events. Statins
act primarily in the liver by inhibiting 3-hydroxy-3-methylglutaryl Coenzyme A reductase (Hmgcr), the rate-limiting
enzyme in the mevalonate pathway. In addition to cholesterol, the mevalonate pathway also produces other
essential molecules including: isopentenyl tRNA, heme A, ubiquinone, dolichol, farnesylated and
geranylgeranylated proteins, and vitamin K2. Despite over three decades of research, development, and clinical
experience with statins, many unanswered questions remain about the physiological role and regulation of the
mevalonate pathway in the liver. Critical gaps in knowledge include: 1) which nonsterol metabolites are most
sensitive to depletion, 2) the necessity of the different mevalonate-derived metabolites for hepatocyte function,
3) the precise identity of nonsterol regulatory molecules, 4) genetic factors that determine individual variation in
LDL-C lowering, and 5) the mechanisms by which statins increase the risk of type II diabetes. Our long-term goal
is understand the physiological mechanisms controlling the mevalonate pathway and statin responsiveness, in
order to enable personalized medicine and identify new drug targets. We propose three Specific Aims: 1) Define
which isoprenoid products are required for hepatocyte viability in vivo, 2) Test the hypothesis that loss of dolichol
is responsible for ER stress-induced apoptosis during potent Hmgcr inhibition, 3) Determine the physiological
effects of statins on human hepatocytes in vivo. Successful completion of these studies will define the essential
mevalonate-derived metabolites in the liver, and improve our understanding of new genes and pathways
underlying statin-related hepatotoxicity and statin responsiveness.

## Key facts

- **NIH application ID:** 10140342
- **Project number:** 5R01DK124477-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** William Raymond Lagor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $532,092
- **Award type:** 5
- **Project period:** 2020-04-06 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140342

## Citation

> US National Institutes of Health, RePORTER application 10140342, Physiological Dissection of the Mevalonate Pathway (5R01DK124477-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140342. Licensed CC0.

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